DESCRIPTION(Adapted from applicant's abstract): We are investigating the molecular basis for substrate recognition and inhibitor action in neuropeptidases. These enzymes play key roles in the generation and inactivation of peptide neurotransmitters and hormones. A better understanding of these enzymes and the development of specific inhibitors may permit novel therapies for psychotic disorders, pain, and drug and alcohol addiction. We study one enzyme, neurolysin, as a model system. Like a number of the neuropeptidases, it is active only on short peptides, and it is able to recognize a diverse but specific set of cleavage sites. This enzyme is known to control the levels of neurotensin, which is one of the most potent analgesics known and is thought to play a role in schizophrenia and depression. Our group has determined a crystal structure of neurolysin, which is a 78kDa zinc metallopeptidase. We now plan to determine crystal structures of the enzyme complexed with peptides and inhibitors to determine the basis for the unusual aspects of its substrate recognition. This structural work will be complemented by a series of functional studies aimed at better defining the features of a good substrate. And finally, we will compare the mechanisms of substrate recognition and inhibitor binding with those of a neuropeptidase from a different enzyme family